There is a desperate need for a new TB vaccine that can prevent active tuberculosis either by preventing infection (prophylactic vaccine) or by preventing the onset or progression of active disease (therapeutic vaccine). A potential new TB vaccine with therapeutic efficacy in animal models was reported in Nature magazine in August of 1999: the heat-shock protein (hsp) 65 DNA vaccine developed with funding from the British Medical Research Council. Administration of this vaccine to animals that were already infected with M. tuberculosis showed substantial efficacy over BCG in reducing bacterial burden in target organs. Moreover, administration of the hspDNA vaccine to infected animals treated with anti-TB drugs eliminated residual bacteria in tissues and prevented relapse of infection in the "Cornell" persistor mouse model of latent tuberculosis. There is considerable excitement in the tuberculosis community about this vaccine, since it provided the first indication that a therapeutic vaccine is even possible. Moreover, the activity reported in the Nature article suggests that the vaccine could help prevent drug resistance by elimination of dormant M. tuberculosis in treated individuals. Before this vaccine is tested for efficacy in man, however, substantial new data on safety and efficacy of heat-shock proteins needs to be generated. The following tasks are envisioned as essential for bringing this vaccine into clinical efficacy trials in man: improving the hsp- containing plasmid for use in humans (removal of antibiotic selections element, replacement of CpG motif, humanization of codons), additional research on the utility and safety of the vaccine (optimal doses for prophylaxis and for therapeutic usage, activity on models of TB disease, determination of immune cells and products stimulated by the vaccine, safety in animal models of autoimmunity), production of clinical grade material (scale up to toxicity and safety testing, formal toxicology studies, formulation of the vaccine) regulatory affairs assistance, and phase I clinical trials design and execution. This challenge grant will concentrate on those aspects of research and development that will move this interesting and potentially useful vaccine into the clinic for assessment of its efficacy.